This invention relates to benzodiazepine tranquilizers.
Bell, in U.S. Pat. No. 3,198,789, discloses 3-chloro derivatives of benzodiazepines as starting materials in the preparation of benzodiazepines with an amino group in the 3-position. He states that the chlorine at the 3-position is very reactive, the compounds reacting at room temperature or below; also that one skilled in the art of organic chemistry would realize that the analogous 3-bromo and 3-iodo compounds could be used in place of the 3-chloro.
Bell, in U.S. Pat. No. 3,296,249, discloses a sequence of reactions that includes the preparation of 3-halo-5-monocyclic-aryl-1,3-dihydro-2H-1,4-benzodiazepin-2-one from the unsubstituted N oxide. These are intermediates for making the 3-hydroxy compounds. The term halo is not defined. He also discloses that the 3-hydroxy compounds can be converted to their corresponding 3-chloro derivatives by treating with an inorganic acid halide, such as thionyl chloride or phosphorous pentachloride. Thionyl fluoride has been unsuccessful as a fluorinating agent with alcohols. [Weichert, K. and Hoffmeister, R., J. Prakt Chem., 10, 290-302 (1960)]
Bell et al., in U.S. Pat. No. 3,296,251, disclose 3-halo-benzodiazepines as intermediates for preparing 3-mercapto-benzodiazepines, and states that a halogen at position 3 is very active: reacting at room temperature with mercapto compounds.
Fryer et al., in U.S. Pat. No. 3,371,083 disclose benzodiazepines substituted in the 3-position with chlorine, bromine, or iodine, which are useful as intermediates.
Fryer et al., in U.S. Pat. No. 3,371,084 disclose 3-halo-1,4-benzodiazepin-2-ones useful as intermediates, where the halogen is preferentially bromine, chlorine, or iodine. Fluorine is not disclosed.
Sternbach, in U.S. Pat. No. 3,450,695, discloses 3-halo-benzodiazepines as intermediates made by treatment of the 3-hydroxy compound with a halogenating agent, such as an inorganic acid halide.
Sternbach et al., in J. Med. Chem., 8, 815 (1965), describe the preparation and some of the reactions of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one.
Bell and Childress, in J. Org. Chem., 27, 1691 (1962), disclose 3,7-dichloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one prepared by reacting the 3-hydroxy compound with thionyl chloride. This 3-chloro derivative, however, was described as extremely reactive: mere warming in alcohol caused decomposition.
Stempel et al., in U.S. Pat. No. 3,321,467, disclose 3-halo-1,4-benzodiazepin-2-one 4-oxides prepared by treating 2-halo-quinazoline 3-oxides with a suitable inorganic base. The halogen is defined as chlorine, bromine, or fluorine; preferably chlorine. The fluorine derivative is not specifically described or exemplified.
No known reference discloses the 3-fluorobenzodiazepines of this invention. Several references teach 3-halo derivatives; mentioning chlorine, bromine, and iodine and specifically exemplifying chlorine. The consensus of the prior art is that 3-halo-benzodiazepines are too reactive and unstable to be practically useful as pharmaceuticals.
There are fundamental differences, however, between chlorine, bromine, and iodine -- the halogens disclosed in the prior art -- and fluorine. It is known in organic chemistry that fluorine is a separate and distinct entity in comparison to chlorine, bromine, and iodine; and is different to such a degree that fluorocarbon chemistry has achieved a completely separate status. Differences between these elements are many. For example:
Fluorine has no low-lying d-orbitals for backbonding as do chlorine, bromine, and iodine, thus leading to less polarizable bonds.
Chlorine, bromine, and iodine can be found in positive valence states (ClO.sub.4, BrO.sub.3, and I.sub.2 O.sub.5) whereas fluorine cannot.
The well-known "haloform" reaction occurs with bromine, chlorine, and iodine, but not with fluorine.
Metal-fluorides differ from metal-chlorides, -bromides, and -iodides: for example, the solubility of silver fluoride in water is one million times greater than the solubility of silver-chloride, -bromide, and -iodide.
Many authorities have noted and recognized the differences between fluorine and halogens. For example:
Sheppard and Sharts, in "Organic Chemistry", W. A. Benjamin (1969) devote the first two chapters to the differences between fluorine and the halogens.
Cotton and Wilkinson, in "Advanced Inorganic Chemistry", Interscience (1962) discuss fluorine compounds in Chapter 14, and chlorine, bromine, and iodine compounds in Chapter 22.
Roberts and Caserio in "Basic Principles of Organic Chemistry", W. A. Benjamin (1964) in Chapter 17, covers chlorine, bromine, and iodine compounds under headings "Alkyl Halides", "Alkenyl Halides", "Cycloalkyl Halides", and "Polyhalogen Compounds". Fluorine compounds are covered under "Fluorinated Alkanes."
Accordingly, under modern chemical practice, fluorine has acquired a separate status, and therefore it is incorrect to conclude that mention of the halogens chlorine, bromine, or iodine necessarily suggests fluorine.
In marked contrast to the 3-chloro-benzodiazepines of the prior art, which Bell and Childress said were too unstable to even give satisfactory analytical results, the 3-fluoro-benzodiazepines of this invention are surprisingly stable against hydrolysis by both aqueous acids and bases, making them especially suitable as pharmaceuticals.
A number of benzodiazepines are well-known useful tranquilizers, muscle-relaxants, and sedatives. Metabolic studies with several of these compounds, including diazepam [Schwartz, M. A. et al., J. Pharmacol. Exp. Ther., 149, 423 (1965)], flurazepam [Schwartz, M. A. and Postma, E. J Pharm. Sci., 59, 1800 (1970)], and nitrazepam [Rieder, J. and Wendt, G., "Benzodiazepines", Garattini, S., Mussini, E., and Randall, L. O., eds., 799, Raven Press, New York (1973)], have shown that they are metabolized in man and other animals by oxidative attack at the 3-position. Substitution with fluorine in this 3-position appears to retard this metabolic pathway, resulting in more potent activity for the 3-fluoro derivatives of this invention.